The present invention relates to pharmacologic agents, and more particularly to a lignosulfonate based pharmacologic agent having anti-coagulant and anti-thrombotic activity.
Thrombophlebitis, which involves blood clotting in the deep veins of the leg, remains one of the major post-operative surgical complications. Thrombophlebitis accounts for approximately one death in every 100 major operations and is also responsible for the death of many debilitated patients, patients in hospitals for periods of prolonged bed rest, and patients who have fractured hips or neurosurgical conditions. Thrombophlebitis is also a major complication of pregnancy and oral contraceptives. The danger of thrombophlebitis is that the thrombus or blood clot may result in morbidity of the leg or more importantly the clot may migrate to the lung resulting in a pulmonary embolism and subsequent death by blocking lung blood flow and oxygen exchange in the lung.
At present, patients in whom a phlebitis develops are given anti-coagulation therapy to prevent clot growth as well as new clot formation. The problem with an anti-coagulant is that it frequently results in undesirable excess bleeding in the patient. An anti-coagulant is typically used, however, because there is at present no known anti-thrombotic agent i.e. blood clot formation preventor, which isn't also an anti-coagulant.
The anti-coagulant heparin is currently widely utilized as a clot formation preventor, and is administered only by injection. Heparin is degraded in the gastrointestinal tract and must be replenished intravenously or via subcutaneous injection. Fortunately, if excess bleeding in a patient occurs with heparin, an intravenous antidote, namely protamine, may be administered to stop the action of heparin.
There are also orally administered anti-coagulants such as Coumadin and Warfarin. However, oral anti-coagulants take approximately 72 hours to build to a desired performance level, and the antidote, Vitamin K and plasma transfusion, which can reverse the anticoagulancy effect, take many hours to work.
A drug available from the Sandoz Company, under the trademark Embolex has recently become available and is a blend of heparin and dihydroergotamine or DHE. Embolex causes veno-constriction which decreases venous pooling and therefore stasis and risks of stasis and thrombosis. There are potential side effects such as gangrene because the product can also cause arterial spasms and its heparin component can cause bleeding.
Recently, some additional drugs have become available which help dissolve blood clots such as streptokinase, urokinase and tissue plasminogen activator. These compounds can also result in bleeding. Furthermore these drugs have not been used to prevent phlebitis.
In a study entitled "Heparin-Like Anti-coagulant Action of Sulfonated Lignins From Commercial Waste Sulfite Liquor", by T. A. Loomis and R. E. Beyer, published in The Journal of Pharmacology and Experimental Therapeutics, Vol. 109, pages 21-25, 1953, the anti-coagulant effect of sodium lignin sulfonate was demonstrated in mongrel dogs. However, acute toxicity was observed in that the dogs experienced behavioral changes as well as increased salivation and instability. Accordingly, Loomis and Beyer concluded that although an anti-coagulant effect could be achieved using sulfonated lignin fractions, the acute toxicity observed made the sulfonated lignin fractions unsatisfactory for use as a substitute for heparin in clinical anti-coagulant therapy thus limiting their value.
Additionally, Loomis and Beyer's study did not evaluate, or even consider, the antithrombotic without anticoagulancy aspect of sodium lignin sulfonate. Furthermore, it has been found that compounds prepared by methodology similar to that utilized by Loomis and Beyer demonstrate adverse effects on blood components, e.g. platelet aggregation, which would render such compounds unsatisfactory for use as antithrombotic agents or anticoagulants.